Muscle mitochondrial bioenergetic capacities are associated with multimorbidity burden in older adults: the Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age =76.4, 56.5% women, 85.9% non-Hispanic white) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95%CI]) for the likelihood of greater multimorbidity (four levels: 0 conditions, N=332; 1 condition, N=299; 2 conditions, N=98; or 3+ conditions, N=35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. RESULTS: Lower oxidative phosphorylation supported by fatty acids and/or complex-I and -II linked carbohydrates (e.g., Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR=1.32[1.13,1.54]) and separately with diabetes mellitus (OR=1.62[1.26,2.09]), depressive symptoms (OR=1.45[1.04,2.00]) and possibly chronic kidney disease (OR=1.57[0.98,2.52]) but not significantly with other conditions (e.g., cardiac arrhythmia, chronic obstructive pulmonary disease). CONCLUSIONS: Lower muscle mitochondrial bioenergetic capacities was associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and is more strongly related to some conditions than others.

Cardiopulmonary Exercise Testing in a Prospective Multicenter Cohort of Older Adults.

PURPOSE: Cardiorespiratory fitness (CRF) measured by peak oxygen consumption (VO 2 peak) declines with aging and correlates with mortality and morbidity. Cardiopulmonary Exercise Testing (CPET) is the criterion method to assess CRF, but its feasibility, validity and reliability in older adults is unclear. Our objective was to design and implement a dependable, safe and reliable CPET protocol in older adults. METHODS: VO 2 peak was measured by CPET, performed using treadmill exercise in 875 adults ≥70 years in the Study of Muscle, Mobility and Aging (SOMMA). The protocol included a symptom-limited peak (maximal) exercise and two submaximal walking speeds. An adjudication process was in place to review tests for validity if they met any prespecified criteria [VO 2 peak < 12.0 ml/kg/min; maximum heart rate (HR) <100 bpm; respiratory exchange ratio (RER) <1.05 and a rating of perceived exertion <15]. A subset (N = 30) performed a repeat test to assess reproducibility. RESULTS: CPET was safe and well tolerated, with 95.8% of participants able to complete the VO 2 peak phase of the protocol. Only 56 (6.4%) participants had a risk alert and only two adverse events occurred: a fall and atrial fibrillation. Mean ± SD VO 2 peak was 20.2 ± 4.8 mL/kg/min, peak HR 142 ± 18 bpm, and peak RER 1.14 ± 0.09. Adjudication was indicated in 47 tests; 20 were evaluated as valid, 27 as invalid (18 data collection errors, 9 did not reach VO 2 peak). Reproducibility of VO 2 peak was high (intraclass correlation coefficient = 0.97). CONCLUSIONS: CPET was feasible, effective and safe for older adults, including many with multimorbidity or frailty. These data support a broader implementation of CPET to provide insight into the role of CRF and its underlying determinants of aging and age-related conditions.

Role of Cardiorespiratory Fitness and Mitochondrial Oxidative Capacity in Reduced Walk Speed of Older Adults with Diabetes.

Cardiorespiratory fitness and mitochondrial oxidative capacity are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial oxidative capacity on walking speed in older adults with diabetes has not been clearly defined. We examined differences in cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity between older adults with and without diabetes as well as determine their relative contribution to slower walking speed in older adults with diabetes. Participants with diabetes (n=159) had lower cardiorespiratory fitness and mitochondrial respiration in permeabilized fiber bundles when compared to those without diabetes (n=717), following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walk speed between older adults with and without diabetes. Additional adjustments with BMI and co-morbidities further explained the group differences in walk speed. Cardiorespiratory fitness and skeletal muscle mitochondrial oxidative capacity contribute to slower walking speeds in older adults with diabetes.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Associations of accelerometry-measured and self-reported physical activity and sedentary behavior with skeletal muscle energetics: The Study of Muscle, Mobility and Aging (SOMMA).

BACKGROUND: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to offset these declines in older adults. Yet, many studies reporting these effects were based on self-reported PA or structured exercise interventions. Therefore, we examined the associations of accelerometry-measured and self-reported PA and sedentary behavior (SB) with skeletal muscle energetics and explored the extent to which PA and sedentary behavior would attenuate the associations of age with muscle energetics. METHODS: As part of the Study of Muscle, Mobility and Aging, enrolled older adults (n = 879), 810 (age = 76 ± 5 years old, mean ± SD; 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maximal oxidative phosphorylation (maxOXPHOS)) and in vivo by 31phosphorus magnetic resonance spectroscopy (maximal adenosine triphosphate (ATPmax)). Accelerometry-measured sedentary behavior, light activity, and moderate-to-vigorous PA (MVPA) were assessed using a wrist-worn ActiGraph GT9X over 7 days. Self-reported sedentary behavior, MVPA, and all PA were assessed with the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations of sedentary behavior and PA with muscle energetics, as well as the attenuation of the age/muscle energetics association by MVPA and sedentary behavior. As a sensitivity analysis, we also examined activPAL-measured daily step count and time spent in sedentary behavior and their associations with muscle energetics. RESULTS: Every 30 min/day more of ActiGraph-measured MVPA was associated with 0.65 pmol/(s × mg) higher maxOXPHOS and 0.012 mM/s higher ATPmax after adjusting for age, site/technician, and sex (p < 0.05). Light activity was not associated with maxOXPHOS or ATPmax. Meanwhile, every 30 min/day spent in ActiGraph-measured sedentary behavior was associated with 0.39 pmol/s × mg lower maxOXPHOS and 0.006 mM/s lower ATPmax (p < 0.05). Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors, and multimorbidity. CHAMPS MVPA and all PA yielded similar associations with maxOXPHOS and ATPmax (p < 0.05), but sedentary behavior did not. Higher activPAL step count was associated with higher maxOXHPOS and ATPmax (p < 0.05), but time spent in sedentary behavior was not. Additionally, age was significantly associated with muscle energetics for men only (p < 0.05); adjusting for time spent in ActiGraph-measured MVPA attenuated the age association with ATPmax by 58% in men. CONCLUSION: More time spent in accelerometry-measured or self-reported daily PA, especially MVPA, was associated with higher skeletal muscle energetics. Interventions aimed specifically at increasing higher intensity activity might offer potential therapeutic interventions to slow age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness With Liver Fat Among Older Adults.

BACKGROUND: Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults. METHODS: We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (magnetic resonance imaging), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate-to-vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women-≥88 cm, men-≥102 cm) and gender. RESULTS: Among older adults aged 75 (interquartile range: 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall (N = 362) but were positively associated among participants with a high waist circumference (ß: 25.2; 95% confidence intervals [95% CI]: 11.7, 40.4; p = .0002; N = 160). Muscle fat infiltration and liver fat were positively associated (ß: 15.2; 95% CI: 6.8, 24.3; p = .0003; N = 378). Carbohydrate-supported maximum oxidative phosphorylation (before adjustment) and VO2 peak (after adjustment; ß: -12.9; 95% CI: -20.3, -4.8; p = .003; N = 361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (ß: -4.0; 95% CI: -11.6, 4.2; p = .32; N = 321). CONCLUSIONS: Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.

Associations Between D3Cr Muscle Mass and Magnetic Resonance Thigh Muscle Volume With Strength, Power, Physical Performance, Fitness, and Limitations in Older Adults in the SOMMA Study.

BACKGROUND: How magnetic resonance (MR) derived thigh muscle volume and deuterated creatine dilution derived muscle mass (D3Cr muscle mass) differentially relate to strength, fitness, and other functions in older adults-and whether associations vary by sex-is not known. METHODS: Men (N = 345) and women (N = 482) aged ≥70 years from the Study of Muscle, Mobility, and Aging completed leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures, study outcomes, and sex interactions. RESULTS: D3Cr muscle mass and MR thigh muscle volume were correlated (men: r = 0.62, women: r = 0.51, p < .001). Each standard deviation (SD) decrement in D3Cr muscle mass was associated with lower 1-repetition max strength (-14 kg men, -4 kg women, p < .001 for both; p-interaction = .003) and lower VO2peak (-79 mL/min men, -30 mL/min women, p < .001 for both, p-interaction: .016). Each SD decrement in MR thigh muscle volume was also associated with lower strength (-32 kg men, -20 kg women, p < .001 for both; p-interaction = .139) and lower VO2peak (-217 mL/min men, -111 mL/min women, p < .001 for both, p-interaction = .010). There were associations, though less consistent, between muscle size or mass with physical performance and function; associations varied by sex. CONCLUSIONS: Less muscle-measured by either D3Cr muscle mass or MR thigh muscle volume-was associated with lower strength and fitness. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies.

Understanding the variation in exercise responses to guide personalized physical activity prescriptions.

Understanding the factors that contribute to exercise response variation is the first step in achieving the goal of developing personalized exercise prescriptions. This review discusses the key molecular and other mechanistic factors, both extrinsic and intrinsic, that influence exercise responses and health outcomes. Extrinsic characteristics include the timing and dose of exercise, circadian rhythms, sleep habits, dietary interactions, and medication use, whereas intrinsic factors such as sex, age, hormonal status, race/ethnicity, and genetics are also integral. The molecular transducers of exercise (i.e., genomic/epigenomic, proteomic/post-translational, transcriptomic, metabolic/metabolomic, and lipidomic elements) are considered with respect to variability in physiological and health outcomes. Finally, this review highlights the current challenges that impede our ability to develop effective personalized exercise prescriptions. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) aims to fill significant gaps in the understanding of exercise response variability, yet further investigations are needed to address additional health outcomes across all populations.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

BACKGROUND: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. METHODS: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy for the maximal rate of adenosine triphosphate recovery (ATPmax) after an acute bout of exercise, and ex vivo by High-Resolution Respirometry for the maximal rate of complex I and II supported oxygen consumption (MaxOXPHOS) in permeabilized muscle fibers from the vastus lateralis. RESULTS: At least 1 fall was reported in 28.7% of SOMMA participants in the first year of the study, with 12% of older adults reporting recurrent falls (2+). Individuals who experienced recurrent falls had a slower 400-m walk gait speed (1.0 ± 0.2 vs 1.1 ± 0.2, p < .001), reported fewer alcoholic drinks per week in the past year (2.4 ± 4.3 vs 2.8 ± 4.4, p = .054), and took a significantly greater number of medication in the 30 days before their baseline visit (5.6 ± 4.4 vs 4.2 ± 3.4, p < .05). A history of falls was reported in 63% of individuals who experienced recurrent falls in the first year of the study compared to 22.8% who experienced 1 or fewer falls. MaxOXPHOS was significantly lower in those who reported recurrent falls (p = .008) compared to those with 1 or fewer falls, but there was no significant difference in ATPmax (p = .369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (risk ratio = 1.33, 95% confidence interval = 1.02-1.73, p = .033). However, covariates accounted for the increased risk. CONCLUSIONS: Mitochondrial energetics were largely unrelated to fall risk in older adults when accounting for variables, suggesting that the complex etiology of falls may not be related to a single "hallmark of aging" biological pathway.

Vigor to Frailty As a Continuum-A New Approach in the Study of Muscle, Mobility, and Aging Cohort.

BACKGROUND: Frailty can occur in older adults without disability or multimorbidity. Current methods focus on the most frail, but poorly discriminate among those "not frail." METHODS: The Study of Muscle, Mobility, and Aging (SOMMA) included 879 adults aged 70 years and older without mobility disability. We operationalized frailty domains using: peak oxygen consumption (endurance), digit symbol substitution test (speed), leg power (strength), perceived fatigability, D3 creatine dilution (sarcopenia), and accelerometry (sedentary behavior) to construct a frailty score of 0-12 summing tertiles (0-2) of each component. We used linear or logistic regression with and without adjustment for confounders to examine associations with age, reported, and performance function. RESULTS: The SOMMA frailty score distribution was broad and strongly associated with age (r = 0.33, p < .0001). Each point was associated with a 30%-50% higher odds of having reported difficulty with activities of daily living or mobility. After grouping the total score (0-3, 4-7, and 8-12) those in the highest group were 9-31 times more likely to have functional limitation, and at least 8 times more likely to have poorer function after full adjustment. Higher scores identified those less likely to report ease of walking or higher physical activity. Peak oxygen consumption, leg power, fatigability, and digit symbol score contributed most to these associations. CONCLUSIONS: The SOMMA frailty score characterizes frailty as a continuum from frail to vigorous with assessments that are amenable to change. Associations with age and function suggest utility for distinguishing a wide range of vigor and vulnerability in relatively well-functioning older adults.

Usual-paced 400 m long distance corridor walk estimates cardiorespiratory fitness among older adults: The Study of Muscle, Mobility and Aging.

BACKGROUND: Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400 m long distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF. The purpose of this study was to develop and validate an estimating equation to estimate VO2 peak from average 400 m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). METHODS: At baseline, women (58%) and men age 70 years and older enrolled in SOMMA (N = 820, 76.2 ± 4.9 years, 86% Non-Hispanic White) completed a 400 m LDCW (400 m WS = 400 m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO2 peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400 m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). RESULTS: Mean VO2 peak was 20.2 ± 4.8 mL/kg/min and mean 400 m WS was 1.06 ± 0.2 m/s. Each 0.05 m/s increment in 400 m WS was associated with a 0.40 mL/kg/min higher VO2 peak after covariate adjustment. An estimating equation including 400 m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO2 peak values. Bland-Altman plot and regression analyses indicated predicted VO2 peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among the highly fit. CONCLUSIONS: Usual-paced 400 m LDCW strongly correlates with direct measures of CRF during CPET in older adults with lower fitness and can be used to test both fitness and function.

Skeletal Muscle Energetics Explain the Sex Disparity in Mobility Impairment in the Study of Muscle, Mobility and Aging.

The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery (SPPB) score ≤8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (eg, Maximal Complex I&II OXPHOS: Women = 55.06 ± 15.95; Men = 65.80 ± 19.74; p < .001) and in individuals with mobility impairment compared to those without (eg, Maximal Complex I&II OXPHOS in women: SPPB ≥ 9 = 56.59 ± 16.22; SPPB ≤ 8 = 47.37 ± 11.85; p < .001). Muscle energetics were negatively associated with age only in men (eg, Maximal ETS capacity: R = -0.15, p = .02; age/sex interaction, p = .04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, odds ratio [OR]age-adjusted = 1.78, 95% confidence interval [CI] = 1.03, 3.08, p = .038; 80+ age group, ORage-adjusted = 1.05, 95% CI = 0.52, 2.15, p = .89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.

Associations of Skeletal Muscle Mass, Muscle Fat Infiltration, Mitochondrial Energetics, and Cardiorespiratory Fitness with Liver Fat Among Older Adults.

Background: Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults. Methods: We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D 3 -creatine dilution), muscle fat infiltration (MRI), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO 2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate to vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: women-≥88 cm, men-≥102 cm) and gender. Results: Among older adults aged 75 (IQR 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall but were positively associated among participants with a high waist circumference (ß: 25.2; 95%CI 11.7, 40.4; p =.0002; N=362). Muscle fat infiltration and liver fat were positively associated (ß: 15.2; 95%CI 6.8, 24.3; p =.0003; N=378). Carbohydrate-supported maximum oxidative phosphorylation and VO 2 peak (adjusted ß: -12.9; 95%CI -20.3, -4.8; p =0.003; N=361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (ß: -4.0; 95%CI -11.6, 4.2; p =0.32; N=321). Conclusions: Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted.

The association of skeletal muscle energetics with recurrent falls in older adults within the Study of Muscle, Mobility and Aging (SOMMA).

Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31 P Magnetic Resonance Spectroscopy (MRS) (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS). Results: SOMMA participants who reported recurrent falls (12%) had a slower 400m walk gait speed compared to those with 0-1 falls (1.0 +/-0.2 vs. 1.1 +/-0.2, p<.001) and took a greater number of medication in the 30 days before their baseline visit (5.6 +/-4.4 vs. 4.2 +/-3.4, p<0.05). MaxOXPHOS was significantly lower in those who reported recurrent falls (p=0.008) compared to those with one or fewer falls, but there was no significant difference in ATPmax (p=0.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (RR=1.33, 95% CI= 1.02-1.73, p=0.033). However, covariates accounted for the increased risk. Conclusions: Ex vivo maximal muscle mitochondrial energetics were lower in older adults who experienced recurrent falls, but covariates accounted for its association with recurrent fall risk, suggesting this "hallmark of aging" may not be directly implicated in the complex etiology of falls.

Signatures of Cysteine Oxidation on Muscle Structural and Contractile Proteins Are Associated with Physical Performance and Muscle Function in Older Adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (r = 0.48) between a higher oxidation level of 8 Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impair muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Associations of Objective and Self-Reported Physical Activity and Sedentary Behavior with Skeletal Muscle Energetics: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to counteract these declines in older adults. Yet, many studies were based on self-reported PA or structured exercise interventions. We examined the associations of objective daily PA and sedentary behavior (SB) with skeletal muscle energetics and also compared with self-reported PA and SB. We also explored the extent to which PA would attenuate the associations of age with muscle energetics. Methods: Among the Study of Muscle, Mobility and Aging (SOMMA) enrolled older adults, 810 (mean age=76±5, 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maxOXPHOS) and in vivo by 31 Phosphorus magnetic resonance spectroscopy (ATP max ). Objective PA was measured using the wrist-worn ActiGraph GT9X over 7-days to capture sedentary behavior (SB), light, and moderate-to-vigorous PA (MVPA). Self-reported SB, MVPA, and all exercise-related PA were assessed with The Community Healthy Activities Model Program for Seniors questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations between SB, PA and muscle energetics, and the attenuation of the age / muscle energetic association by PA. Results: Every 30 minutes more objective MVPA was associated with 0.65 pmol/s*mg higher maxOXPHOS and 0.012 mM/sec higher ATP max , after adjustment for age, site/technician and sex. More time spent in objective light+MVPA was significantly associated with higher ATP max , but not maxOXPHOS. In contrast, every 30 minutes spent in objective SB was associated with 0.43 pmol/s*mg lower maxOXPHOS and 0.004 mM/sec lower ATP max . Only associations with ATP max held after further adjusting for socioeconomic status, body mass index, lifestyle factors and multimorbidities. Self-reported MVPA and all exercise-related activities, but not SB, yielded similar associations with maxOXPHOS and ATP max . Lastly, age was only significantly associated with muscle energetics in men. Adjusting for objective time spent in MVPA attenuated the age association with ATP max by nearly 60% in men. Conclusion: More time spent in daily PA, especially MVPA, were associated with higher muscle energetics. Interventions that increase higher intensity activity might offer potential therapeutic interventions to slow the age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics.

Usual-Paced 400m Long Distance Corridor Walk Estimates Cardiorespiratory Fitness among Older Adults: The Study of Muscle, Mobility and Aging (SOMMA).

Background: Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400m long-distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF among populations unable to complete maximal intensity testing. The purpose of this study was to develop and validate an estimating equation to estimate VO 2 peak from average 400m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). Methods: At baseline, participants (N=820, 76.2±4.9 years, 58% Women, 86% Non-Hispanic White) completed a 400m LDCW (400m WS=400m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO 2 peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). Results: Mean VO 2 peak was 20.2±4.8 mL/kg/min and mean 400m WS was 1.06±0.2 m/s. Each 0.05 m/s increment in 400m WS was associated with a 0.40 mL/kg/min higher VO 2 peak after adjustment for covariates. An estimating equation including 400m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO 2 peak values. Bland-Altman plot and regression analyses indicated predicted VO 2 peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among those with CPET VO 2 peak ≥25 mL/kg/min. Conclusions: Usual-paced 400m LDCW strongly correlates with direct measures of cardiorespiratory fitness during CPET in older adults with lower fitness and can be used to test both fitness and function.

Associations between D3Cr muscle mass and MR thigh muscle volume with strength, power, physical performance, fitness, and limitations in older adults in the SOMMA study.

Background: Different measures to assess muscle size - magnetic resonance (MR) derived thigh muscle volume and d3-creatine dilution derived muscle mass (D3Cr muscle mass) - may have similar associations with strength, power, physical performance, fitness, and functional limitations in older adults. Methods: Men (N=345) and women (N=482) aged ≥70 years from the Study of Muscle, Mobility and Aging completed exams including leg extension strength (1-repetition max) and cardiopulmonary exercise testing to assess fitness (VO2peak). Correlations and adjusted regression models stratified by sex were used to assess the association between muscle size measures and study outcomes; we tested for sex interactions. Results: D3Cr muscle mass and MR thigh muscle volume were correlated (men: r=0.62, women: r=0.51, p<.001). Lower D3Cr muscle mass and lower MR thigh muscle volume were associated with lower strength and lower VO2peak in both men and women; D3Cr muscle mass was more strongly associated with strength in men than in women (p-int<0.05). There were correlations, though less consistent, between muscle size or mass with physical performance and function. Associations between the muscle size measures and the study outcomes occasionally varied by sex, and associations of MR thigh muscle volume were, at times, slightly more strongly associated with the study outcomes than was D3Cr muscle mass. Conclusions: Less muscle -measured by either D3Cr muscle mass or MR thigh muscle volume - was associated with lower strength and worse performance. Varied associations by sex and assessment method suggest consideration be given to which measurement to use in future studies.

Role of Cardiorespiratory Fitness and Mitochondrial Energetics in Reduced Walk Speed of Older Adults with Diabetes in the Study of Muscle, Mobility and Aging (SOMMA).

Rationale: Cardiorespiratory fitness and mitochondrial energetics are associated with reduced walking speed in older adults. The impact of cardiorespiratory fitness and mitochondrial energetics on walking speed in older adults with diabetes has not been clearly defined. Objective: To examine differences in cardiorespiratory fitness and skeletal muscle mitochondrial energetics between older adults with and without diabetes. We also assessed the contribution of cardiorespiratory fitness and skeletal muscle mitochondrial energetics to slower walking speed in older adults with diabetes. Findings: Participants with diabetes had lower cardiorespiratory fitness and mitochondrial energetics when compared to those without diabetes, following adjustments for covariates including BMI, chronic comorbid health conditions, and physical activity. 4-m and 400-m walking speeds were slower in those with diabetes. Mitochondrial oxidative capacity alone or combined with cardiorespiratory fitness mediated ∼20-70% of the difference in walk speed between older adults with and without diabetes. Further adjustments of BMI and co-morbidities further explained the group differences in walk speed. Conclusions: Skeletal muscle mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speeds in older adults with diabetes. Cardiorespiratory fitness and mitochondrial energetics may be therapeutic targets to maintain or improve mobility in older adults with diabetes. ARTICLE HIGHLIGHTS: Why did we undertake this study? To determine if mitochondrial energetics and cardiorespiratory fitness contribute to slower walking speed in older adults with diabetes. What is the specific question(s) we wanted to answer? Are mitochondrial energetics and cardiorespiratory fitness in older adults with diabetes lower than those without diabetes? How does mitochondrial energetics and cardiorespiratory fitness impact walking speed in older adults with diabetes? What did we find? Mitochondrial energetics and cardiorespiratory fitness were lower in older adults with diabetes compared to those without diabetes, and energetics, and cardiorespiratory fitness, contributed to slower walking speed in those with diabetes. What are the implications of our findings? Cardiorespiratory fitness and mitochondrial energetics may be key therapeutic targets to maintain or improve mobility in older adults with diabetes.